DESCRIPTION: (Investigator's abstract) Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is a cytokine that stimulates proliferation and differentiation of hematopoietic progenitor cells. Recombinant human GM-CSF is used to stimulate neutrophil production in patients with neutropenia resulting from myelosuppressive chemotherapy. Recombinant human GMCSF had world-wide sales of approximately $100 million during 1997, a 20 percent increase from 1996. We propose to create modified GM-CSF proteins that are equal or superior to natural GM-CSF at stimulating granulocyte/monocyte formation In vivo, but which require less frequent dosing, on the order of once per week or once every other week. During Phase I we identified sites in GM-CSF that can be modified without affecting the protein's in vitro bioactivity. During Phase II, we will manufacture sufficient quantities of the modified GM-CSF proteins for testing in animal models of neutropenia. The improved characteristics of the novel GM-CSF proteins will reduce the amount of GM-CSF required per patient, improve patient compliance and quality of life and result in considerable cost savings to patients and healthcare providers. Information gained from these studies will aid in creating long-acting versions of structurally related cytokines and growth factors for use in treating cancer, infectious disease and hematopoietic disorders. PROPOSED COMMERCIAL APPLICATION: Recombinant human GM-CSF is used to restore neutrophil production in patients with neutropenia resulting from chemotherapy or bone marrow transplantation. Recombinant GM-CSF had world-wide sales in excess of $100 million in 1997. The modified GM-CSF proteins under development will require much less frequent dosing, providing significant cost savings to patients and healthcare providers. Additional potential benefits include improved drug efficacy and improved patient quality of life.